title: γ-Glutamyltransferase catabolism of S-nitrosoglutathione modulates IL-8 expression in cystic fibrosis bronchial epithelial cells.
abstract: S-nitrosoglutathione (GSNO) is an endogenous nitrosothiol involved in several pathophysiological processes. A role for GSNO has been envisaged in the expression of inflammatory cytokines such as IL-8; however, conflicting results have been reported. γ-Glutamyltransferase (GGT) enzyme activity can hydrolyze the γ-glutamyl bond present in the GSNO molecule thus greatly accelerating the release of bioactive nitric oxide. Expression of GGT is induced by oxidative stress, and activated neutrophils contribute to GGT increase in cystic fibrosis (CF) lung exudates by releasing GGT-containing microvesicles. This study was aimed at evaluating the effect of GSNO catabolism mediated by GGT on production of IL-8 in CF transmembrane regulation protein-mutated IB3-1 bronchial cells. The rapid, GGT-catalyzed catabolism of GSNO caused a decrease in both basal and lipopolysaccharide-stimulated IL-8 production in IB3-1 cells, by modulating both NF-κB and ERK1/2 pathways, along with a decrease in cell proliferation. In contrast, a slow decomposition of GSNO produced a significant increase in both cell proliferation and expression of IL-8, the latter possibly through p38-mediated stabilization of IL-8 mRNA. Our data suggest that the differential GSNO catabolism mediated by GGT enzyme activity can downregulate the production of IL-8 in CF cells. Hence, the role of GGT activity should be considered when evaluating GSNO for both in vitro and in vivo studies, the more so in the case of GSNO-based therapies for cystic fibrosis.
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, Medical School, University of Pisa, 56126 Pisa, Italy. Electronic address: alessandro.corti@med.unipi.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corti
authors.affiliation: Cystic Fibrosis Center-Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bergamini
authors.affiliation: Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Menegazzi
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, Medical School, University of Pisa, 56126 Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Piaggi
authors.affiliation: National Research Council of Italy, CNR, Istituto di Chimica dei Composti Organo Metallici-ICCOM-UOS, Pisa, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Bramanti
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, Medical School, University of Pisa, 56126 Pisa, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Scataglini
authors.affiliation: Department of Surgery and Medical, Molecular, and Critical Area Pathology, Medical School, University of Pisa, 56126 Pisa, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Cianchetti
authors.affiliation: Department of Surgery and Medical, Molecular, and Critical Area Pathology, Medical School, University of Pisa, 56126 Pisa, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Paggiaro
authors.affiliation: Cystic Fibrosis Center-Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Melotti
authors.affiliation: Department of Translational Research and New Technologies in Medicine and Surgery, Medical School, University of Pisa, 56126 Pisa, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Pompella
mesh_terms: D015153:Blotting, Western; D001980:Bronchi / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003550:Cystic Fibrosis / Q000378:metabolism*; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000096:biosynthesis*; D020545:Respiratory Mucosa / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026422:S-Nitrosoglutathione / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D026422:S-Nitrosoglutathione; D005723:gamma-Glutamyltransferase
keywords: Cystic fibrosis; Free radicals; IL-8; S-nitrosoglutathione; γ-Glutamyltransferase